Total synthesis of 3,3′,4-tri-O-methylellagic acid from gallic acid

Article abstract of DOI:10.1016/j.tet.2007.07.103

Total synthesis of 3,3′,4-tri-O-methylellagic acid has been described from commercially available gallic acid. Construction of the crucial unsymmetric Ar-Ar bond has been carried out in various methods such as Heck coupling, Heck coupling followed by oxidation or anionic Fries rearrangement, Suzuki cross-coupling, etc., but all the attempts were unsuccessful. Then, finally it has been achieved by intramolecular Ullmann coupling reaction.

Full text of DOI:10.1016/j.tet.2007.07.103

Tetrahedron 63 (2007) 10454–10465
Total synthesis of 3,30,4-tri-O-methylellagic acid from gallic acid
Ashraful Alama and Sadao Tsuboib,
*
aDepartment of Chemistry, Shahjalal University of Science and Technology, Sylhet-3114, Bangladesh
bDepartment of Material and Energy Science, Graduate School of Environmental Science,
Okayama University, Tsushima, Okayama 700-8530, Japan
Received 29 May 2007; revised 25 July 2007; accepted 28 July 2007
Available online 3 August 2007
Abstract—Total synthesis of 3,30,4-tri-O-methylellagic acid has been described from commercially available gallic acid. Construction of the
crucial unsymmetric Ar–Ar bond has been carried out in various methods such as Heck coupling, Heck coupling followed by oxidation or
anionic Fries rearrangement, Suzuki cross-coupling, etc., but all the attempts were unsuccessful. Then, finally it has been achieved by intra-
molecular Ullmann coupling reaction.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
for the synthesis of symmetric derivatives, but not suitable
at all for the synthesis of unsymmetric derivatives. For
example, Ikeda et al.11 and Takasaki et al.8 have reported
the syntheses of 3,30,4-tri-O-methylellagic acid individually
in 2.5% and 8% overall yields, respectively, by methylation
of ellagic acid. Besides the very poor overall yields, the
procedure of methylation is very cumbersome due to the
formation of various methylated products and their separa-
tion is also difficult due to the extremely low solubility of
all these methyl derivatives even in most of the commonly
used polar solvents.
Ellagic acid and its derivatives are very potent for their var-
ious biological activities such as anti-tumor,1 anti-HIV,2
anti-cancer,3 anti-hepatitis,4 anti-oxidant,5 anti-microbial,6
etc. Interestingly these compounds also exhibit free radical
scavenging activity and thus are used in anti-aging supple-
ment.7 Takasaki et al.8 reported the isolation of a variety
of ellagic acid derivatives and their inhibitory effects on Ep-
stein–Barr virus action. They found the enhanced inhibitory
activity of some ellagic acid derivatives than the parent com-
pound ellagic acid. For instance, 3,30,4-tri-O-methylellagic
acid and 3,30,4-tri-O-methylellagic acid-40-acetal are found
to be 50 times more active than the parent ellagic acid. Be-
sides the wide biological activities, these are used as impor-
tant ingredients for anti-aging, skin lightening supplements,
and other skin care cosmetics.9 Earlier we have reported the
isolation of 3,30,4-tri-O-methylellagic acid from Cassia
alata leaf extract,10 and then we were interested in its total
synthesis for the large supply as well as further study of it.
Herein, the total synthesis of 3,30,4-tri-O-methylellagic acid
is described via the construction of unsymmetric Ar–Ar
bond, which has been achieved by the intramolecular Ull-
mann coupling of commercially available gallic acid. This
strategy for the synthesis of 3,30,4-tri-O-methylellagic acid
can also provide a suitable route for the synthesis of other
unsymmetric ellagic acid derivatives such as 3,4,40-tri-O-
methylellagic acid as well as many unsymmetric biaryls,
particularly those highly hindered at ortho-positions. These
biaryls are very important for the syntheses of various natu-
ral products containing the unsymmetric biaryl skeleton.
Unlike the symmetrically substituted 3,30-di-O-methylella-
gic acid 1b, syntheses of unsymmetrically substituted ellagic
acids such as 3,30,4-tri-O-methylellagic acid 1c or 3,4,40-tri-
O-methylellagic acid 1d are more challenging due to the
construction of the required unsymmetric Ar–Ar bond. Syn-
theses and pharmaceutical study of a number of symmetric
and several unsymmetric ellagic acid derivatives have been
reported so far; but all of them were either isolated from nat-
ural species or derivatized from the ellagic acid 1a. The pro-
cess of derivatization of ellagic acid gives satisfactory result
1.1. Formation of unsymmetric Ar–Ar bond by
intermolecular cross-coupling
Among other methods, the 100-year old traditional Ullmann
coupling is yet found to be very useful for the synthesis of
many biaryls. But, most of them are symmetric biaryls and
formation of the unsymmetric biaryls by the Ullmann
cross-coupling is very rare. For the present case other com-
monly used cross-couplings such as reaction between
aromatic Grignard reagents and aromatic halides mediated
* Corresponding author. Tel./fax: +81 86 251 8898; e-mail addresses:
ashraf_sust@yahoo.com; stsuboi6@cc.okayama-u.ac.jp
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.07.103

A. Alam, S. Tsuboi / Tetrahedron 63 (2007) 10454–10465
10455
O
O
O
O
OR1
OR2
OMe
OH
1a. R1= R2= R3= R4= H, Ellagic acid
1b. R1= R3= Me, R2= R4= H
R4O
R3O
MeO
MeO
O
O
O
O
O
O
1c, 3,3',4-tri-O-methylellagic acid
O
OMe
O
O
OMe
OMe
MeO
MeO
HO
1d, 3,4,4'-tri-O-methylellagic acid
Figure 1. Ellagic acid and its derivatives.
MeO
O
O
O
O
O
n
1e, n= 1, 2
by a variety of catalysts12 are not suitable due to the presence
of carbonyl group in both of the aromatics (Chart 1). Simi-
larly, Suzuki cross-coupling between 5 and 6 (Chart 1) is
also not suitable because it requires the use of organometal-
lic reagent for the preparation of boronic acid component.
Besides this, success of the cross-coupling reaction greatly
depends on differences of the electronic environments of
participating components; the higher the difference, the bet-
ter the chance of getting the cross-coupling product. For the
cross-coupling reaction the ratio of the symmetric and un-
symmetric products is also highly dependent on the reaction
conditions.12,13
Intramolecular Ar–Ar bond formation via Heck type intra-
molecular coupling has been applied for the syntheses of
a wide variety of natural products.15 Intramolecular coupling
reaction mediated by Grignard reagent16 or Stille coupling17
are also reported. Takahashi et al.18 and Dai and Martin19
have studied the formation of optically active biaryls by in-
tramolecular coupling utilizing salicyl alcohol and glucoses,
respectively, as template. Considering all the methods
mentioned above, the unsymmetric Ar–Ar bond of 3,30,4-
tri-O-methylellagic acid has been planned to be constructed
as depicted in Chart 1.
1.2. Formation of unsymmetric Ar–Ar bond by
intramolecular coupling
2. Results and discussion
In Chart 1 it has been shown that the ordinary cross-coupling
between aryl bromides 3 and 4 is not suitable as both of them
have the same structural and electronic environments. Thus,
among other probable routes depicted, intramolecular Heck
coupling was chosen first to carry out rather than other
couplings.
Unlike the symmetric Ullmann coupling, the intramolecular
Ullmann coupling is rare and several methods for the intra-
molecular coupling have appeared so far. For example, Lip-
shutz et al.14 developed a method for the synthesis of biaryls
by intramolecular coupling of cyanocuprate intermediates.
OMe
HO
O
MeO
O
MeO
O
OMe
RO
OMe
Br
Br
O
Ullmann Cross
coupling
+
HO
OH
HO
OH
MeO
OH
MeO
O
OH
OMe
OMe
4
OR
O
RO
2
, gallic acid
3
7
OMe
R1
O
OMe
B(OH)2
OR
OMe
O
4
RO
OMe
5, R1= OtBu, CONEt2
O
O
HO
OMe
OMe
MeO
RO
3,3',4-tri-O-methylellagic acid
OR
OMe
1c
OMe
OR
O
Br
X= H
Heck coupling
X= Br
Intramolecular
Ullmann
OMe
6
O
OR
O
C
O
DCC, DMAP
+
X
O
Br
OR
C
O
O
X
OMe
OMe
OR
OMe
HO
O
MeO
MeO
OMe
8, X= H; 9, X= Br
10
OR
OMe
Chart 1. The probable routes for the synthesis of 3,30,4-tri-O-methylellagic acid.

10456
A. Alam, S. Tsuboi / Tetrahedron 63 (2007) 10454–10465
O
OH
Br
O
OH
O
OH
i. K2CO3 (5 eq), MeI (5 eq),
DMF, 50-55 °C, overnight
NaOH aq (1.1 eq),
DBDMH, r.t., 36h, 96%
ii. LiOH, MeOH/ H2O, r.t.,
2 h, 98% in two steps
MeO
OMe
HO
MeO
OH
OMe
OMe
12
OH
OMe
11
2, gallic acid
OMe
OMe
OMe
OMe
O
OMe
O
DCC (1.0 eq),
DMAP (cat.),
Pd(OAc)2, PPh3, NaOAc,
DMA, 130 °C, 12 h
OMe
OMe
O
OMe
OMe
12
+
Br
THF, 0 °C, then
r.t., 6 h, 75%
Pd(PPh3)4, CuI, Et3N,
DMF, 6.5 h
O
MeO
OH
O
O
O
OMe
13
MeO
MeO
OMe
8a
OMe
10a
Scheme 1. Preparation and the Heck coupling of the model key intermediate 8a.
2.1. Formation of unsymmetric Ar–Ar bond via intra-
molecular Heck type coupling
of compound 8a with PdII did not give the desired coupling
product 10a but recovered starting material or reduced de-
brominated product.
At first, the unsymmetric Ar–Ar bond of 3,30,4-tri-O-methyl-
ellagic acid was planned to be synthesized from the intramo-
lecular Heck coupling of compound 8 and thus a similar
model key intermediate 8a was prepared as shown in Scheme
1. Gallic acid 2 was treated with K2CO3 and MeI in DMF at
50–55 ꢀC followed by hydrolysis of the methyl ester by treat-
ing with LiOH in MeOH/H2O (1:1) at room temperature
for 2 h to give the 3,4,5-trimethoxybenzoic acid 11 in
98% yield over two steps. Compound 11 was brominated
with 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) in
1.1 equiv of aqueous NaOH to give the corresponding bro-
mide 12 in 96% yield. Compound 12 was subjected to
esterification with methyl 3-hydroxy-4,5-dimethoxybenz-
oate 13 in the presence of 1.0 equiv of DCC and catalytic
amount of DMAP in THF at room temperature that resulted
in the desired model key intermediate 8a in 75% yield
(Scheme 1).
Not getting the desired coupling product 10a with a variety
of reagents was very much disappointing, though numerous
examples of such coupling have been reported for the syn-
thesis of a variety of natural products.15 Then, literature sur-
vey revealed that among the reported examples of such
coupling, none of them possesses a carbonyl group in one
or both the aromatic rings. Similar disappointing result
was also obtained by Bringmann et al.20 Then, the problem
with carbonyl functionality was planned to be overcome by
any one of the following processes: (i) to convert another
functional group (e.g., CH3) to the carboxylic acid group af-
ter the coupling reaction, or (ii) to construct the required lac-
tone by the remote anionic Fries rearrangement20 (Chart 2).
Between the two routes, the former one was tested first and
for this purpose a model reaction was carried out with com-
pound 8d as shown in Scheme 2.
After the easy access to the key intermediate 8a in good
overall yield from gallic acid 2 (71% overall yield from 2
over four steps), the next crucial step, intramolecular Heck
coupling reaction was unsuccessful. Unfortunately, reaction
In Scheme 2, 2-bromo-3,4,5-trimethoxybenzoic acid 12 was
esterified with the commercially available 3,5-dimethylphe-
nol 16 in the presence of DCC to give the model intermediate
8d in 98% yield. Treatment of compound 8d with Pd(OAc)2
OR
OH
OR
OR
Br
OMe
OMe
OMe
OMe
O
O
lactonyzation
OH
O
O
O
Oxidation
O
O
Heck
Reaction
OR1
CH3
OR1
CH3
O
O
C
O
O
OH
MeO
1c
MeO
14
MeO
10b
MeO
8b
OMe
OMe
OR
OMe
OR
OMe
OR
OR
OMe
O
OMe
OR'
OMe
OR'
OMe
O
O
C
O
NEt2
O
O
Heck
Reaction
OH
Br
+
OH
HO
Fries
Br
NEt2
O
O
O
Rearrangement
O
MeO
MeO
10c
MeO
MeO
OMe
OMe
OMe
MeO
8c
15
Chart 2. Heck coupling followed by oxidation or remote anionic Fries rearrangement.

A. Alam, S. Tsuboi / Tetrahedron 63 (2007) 10454–10465
10457
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
O
KMnO4,
Pd(OAc)2,
PPh3,
DCC (1.1eq),
DMAP (cat),
THF, 0 °C-r.t.,
7 h, 98%
O
O
O
Pyridine/
OMe
Me
OMe
Me
OH Br
OH
O
Br
O
C
12
H2O (1:1),
95-100 °C
O
NaOAc,
130 °C, 24 h
42%
+
O
HO
Me
CO2H
Me
Me
8d
Me
16
10d
14a
Scheme 2. Heck coupling followed by oxidation.
(10 mol %), PPh3, and NaOAc at 130 ꢀC for 24 h in the sim-
ilar way as before gave the desired coupling product 10d in
42% yield (based on 40% recovery of starting material).
Changing of the reaction conditions was not successful to
improve the yield of 10d. Use of small quantity of Pd gave
the same yield of 10d, but higher amount of recovered start-
ing material was found.
2.2. Formation of unsymmetric Ar–Ar bond via intra-
molecular Heck coupling followed by Fries rearrange-
ment
The key intermediate 8e for the remote anionic Fries
rearrangement approach was prepared by esterification of
the functionalized methyl gallate 17 and pyrogallol deriva-
tive 19 (Scheme 3) in the presence of DCC and catalytic
DMAP in THF (86% yield). Deprotection of the acetal group
of pyrogallol part of 8e followed by methyl etherification
gave compound 8f in 84% yield over two steps. Then, both
8e and 8f were subjected to the intramolecular Heck
coupling reaction, but unfortunately the result of the cou-
pling reaction was not satisfactory (Table 1). Reaction of
compounds 8e,f with catalytic amount of PdII in various
reagents and reaction conditions was carried out, but the
yields of 10e,f were very low and they could not be improved
more than 30% using sodium pivalate as base (entry 7).
Herrmann’s catalyst, which is known to be more efficient
for the intramolecular coupling21 than the commonly used
palladium catalyst such as Pd(OAc)2, Pd(PPh3)4, and
After replacing thecarboxyl groupinintermediate 8dbyalkyl
group, the intramolecular Heck coupling was successful, giv-
ing coupling product 10d. But unfortunately, oxidation of 10d
with KMnO4 did not result in the desired oxidation of methyl
group to carboxylic acid functionality (compound 14a) but
some unknown products. In addition to the low yield of 10d
and difficulty of its oxidation, the lower part (16) of the actu-
ally required intermediate 8b (Chart 2) is not easily accessible
from commercially available materials, whereas another in-
termediate 8e (for the second path, Chart 2) could be
prepared easily from pyrogallol as depicted in Scheme 3.
Thus, we were shifted toward the second alternative route,
the remote anionic Fries rearrangement approach.
HO
O
HO
O
CH(OEt)3 (3 eq),
Amberlyst 15E
(5% by wt.),
benzene, reflux,
18 h, 85%
Ref. 26
Br
O
O
HO
O
HO
OH
Et
Et
O
19
OH
18, Pyrogallol
N
OEt
BnO
OH
HO
OMe
17
OH
2, Gallic acid
OBn
OBn
OMe
OMe
O
O
O
Pd, Base (2eq),
DMA, 120 °C,
O
O
NEt2
O
NEt2
DCC (1.1eq), DMAP
+
17
19
Br
O
30% ( 50%
recovery of SM)
(1.1eq), THF, r.t., 6 h, 86%
O
R1O
R1O
OR2
OR2
i. HCl, MeOH, r.t., 4h, 95%
ii. NaH, MeI, DMF, 55 °C,
overnight, 88%
8e, R1-R2= CHOEt
8f, R1= R2= Me
10e, R1-R2= CHOEt
10f, R1= R2= Me
i. HCl, MeOH, r.t.,
ii. NaH, MeI, DMF
OBn
OMe
O
OBn
OMe
O
O
O
i. LDA, THF, reflux
ii. AcOH, reflux
O
NEt2
O
O
O
MeO
MeO
OMe
20
OMe
10f
Scheme 3. Heck coupling followed by Fries rearrangement.

10458
A. Alam, S. Tsuboi / Tetrahedron 63 (2007) 10454–10465
Table 1. Intramolecular Heck coupling of 8e,f
The impure coupling product 10f was then subjected to the
next crucial step, the LDA mediated remote anionic Fries re-
arrangement. But, unfortunately after coming so long a way,
the Fries rearrangement reaction was unsuccessful. Treat-
ment of 10f with LDA in THF resulted in many spots on
TLC and refluxing of the crude product with AcOH resulted
in no desired lactonized product 20 but a complex mixture
(Scheme 3).
Entry
1
8
Reagents and conditions
Result
8e,
R1–R2¼CHOEt
Pd(OAc)2 (0.3 equiv),
PPh3 (0.6 equiv),
NaOPiv (2.0 equiv),
110–120 ꢀC, 1 h
PdCl2(PPh3)2 (0.3 equiv),
NaOAc (3.0 equiv),
DMA, 100 ꢀC, 3 h
Palladacycle (5 mol %),
Cs2CO3 (2 equiv),
DMA, 95 ꢀC, 1 h
Pd(OAc)2 (0.3 equiv),
PPh3 (0.6 equiv),
NaOAc (2.0 equiv),
110–120 ꢀC, 3 h
Palladacycle (5 mol %),
Cs2CO3 (2 equiv),
DMA, 95 ꢀC, 1 h
Pd(OAc)2 (0.15 equiv),
PPh3 (0.45 equiv),
NaOPiv (2.0 equiv),
115–120 ꢀC, 3 h
10e, 4%
2
3
4
8e,
R1–R2¼CHOEt
Complex
mixture
8e,
R1–R2¼CHOEt
Many
spots
2.3. Formation of unsymmetric Ar–Ar bond via Suzuki
cross-coupling
8f,
R1¼R2¼Me
10f, 8%a
After getting the disappointing results for all the attempts
taken so far, there were only two ways in hand, Suzuki
cross-coupling and intramolecular Ullmann coupling. But
both the methods are not much hopeful for the present
case. The Suzuki cross-coupling is not suitable for the highly
crowded aromatics and that of similar reactivities. Besides
this, preparation of boronic acid component 5a requires
the special protection of the carbonyl group. As there was
no other option at that moment, both the methods were ap-
plied for construction of the challenging unsymmetric Ar–
Ar bond for the synthesis of 3,30,4-tri-O-methylellagic acid.
5
6
8f,
R1¼R2¼Me
Complex
mixture
8f,
R1¼R2¼Me
10f, 15%
7
8
8f,
R1¼R2¼Me
Pd(OAc)2 (0.15 equiv),
PPh3 (0.45 equiv),
NaOPiv (2.0 equiv),
120–125 ꢀC, 1 h
Pd(OAc)2 (0.1 equiv),
PPh3 (0.4 equiv),
10f, 30%b
10f, 35%c,d
8f,
R1¼R2¼Me
In Scheme 4, methyl 3,5-dihydroxy-4-methoxybenzoate 21
was converted to the corresponding amide 23 in 92% overall
yield from 21 via 3,5-dibenzyloxy-4-methoxybenzoic acid
22. Lithiation of 23 followed by treatment with B(OMe)3 re-
sulted in the boronic acid 5a in 94% crude yield. Protection
of the remaining hydroxy group of methyl 2-bromo-3-
hydroxy-4,5-dimethoxybenzoate 2425 as methoxymethyl
ether (MOM) gave the bromide component 6 in 95% yield.
But again unfortunately, after the preparation of boronic acid
5a and the bromide 6 in good overall yields from the same
starting material 21, the Suzuki cross-coupling was unsuc-
cessful and no coupling product 7a was found to be formed.
Actually the Suzuki cross-coupling of such highly ortho-
substituted compounds has not appeared so far, though
a few reports for the coupling of moderately crowded aro-
matics have been reported.22
NaOPiv (2.0 equiv),
120 ꢀC, 50 min
a
Based on 27% recovered starting material.
Based on 30% recovered starting material.
Based on 58% recovered starting material.
Product contained some unknown impurities that were not possible to
separate.
b
c
d
Pd2(dba)3, did not give better yield in the present case
and the crude product showed many spots on TLC
(entries 3 and 5). Use of less amount of PdII was found to
increase the yield only a little (entry 8), and the product
was found to contain an unknown substance that was
not possible to separate by successive column chro-
matography or on preparative thin layer chromatography
(PTLC).
O
OMe
O
OH
O
NEt2
i. K2CO3 (3 eq), BnCl (3 eq),
DMF, 55-60 °C, 12 h, 98%
i. SOCl2, DMF (Cat), reflux
ii. LiOH (4 eq), MeOH/H2O
(4:1), 50 °C, 2h, 96%
ii. HNEt2(1.2 eq), Et3N
(1.2 eq), Et2O, 0 °C-r.t.,
4 h, 98% over 2 steps
HO
BnO
BnO
OH
OBn
OBn
OBn
OMe
21
OMe
22
OMe
23
O
NEt2
sBuLi (1.1 eq), TMEDA (1.1
eq), THF, -78 °C-r.t.; B(OMe)3
B(OH)2
23
OMe
(2 eq), r.t., overnight,
94%, crude yield
BnO
BnO
OBn
O
OMe
OMe
5a
Suzuki cross
coupling
Et2N
O
O
OMe
O
OMe
Br
MOMCl (2 eq),
K2CO3 (2 eq),
MeO
OMOM
Br
OMe
7a
DMF, r.t.,
overnight, 95%
MeO
OH
MeO
OMOM
OMe
24
OMe
6
Scheme 4. Preparation of boronic acid component and the Suzuki cross-coupling.

A. Alam, S. Tsuboi / Tetrahedron 63 (2007) 10454–10465
10459
OH
OMe
O
OR1
MeO
R2O
OMe
OMe
O
O
O
O
C
O
OR1
O
O
Br
Br
Br
O
Br
R1O
MeO
O
OMe
OMe
MeO
R1O
MeO
3,3',4-tri-O-methylellagic acid
O
27
OMe
intermediate with
template molecule
intermediate
without template
molecule
9
HO
OH
Br
O
OR
Br
O
HO
salicyl alcohol
R= Me, R1= Bn,
etc., R2= H
+
R1O
OR1
MeO
OR2
R= H, R1= R2= Bn, etc.
indicates the
bond to be formed
OMe
25
OMe
26
Chart 3. Plan for the preparation of intermediates for intramolecular Ullmann coupling.
2.4. Formation of unsymmetric Ar–Ar bond by
intramolecular Ullmann coupling
(30) was prepared using our selective hydrolysis process.25
Treatment of compound 2125 with DBDMH followed by
benzylation and hydrolysis with LiOH in MeOH/H2O at
room temperature resulted in the mixture of bromo carboxy-
lic acid 30 and unhydrolyzed dibromo ester 29 that was sep-
arated by simple column chromatography. The bromo acid
30 was esterified with the phenolic component 24 in the
presence of DCC and DMAP in THF to give the desired
key intermediate 9b in 78% yield.
All the attempts to construct the required unsymmetric
Ar–Ar bond taken so far become failed, and at this stage
the intramolecular Ullmann coupling is the only remaining
way to carry out. This intramolecular Ullmann coupling
can be carried out in two ways: (i). from the key intermediate
9, which can be obtained from esterification between 25 and
26, or (ii) from the key compound 27, which can be obtained
by esterification of 25 and 26 with salicyl alcohol as a tem-
plate molecule (Chart 3).
In Scheme 7, treatment of key intermediate 9b with ordinary
copper powder in DMF at 110 ꢀC for 3 h and then at 180 ꢀC
for 18 h gave the corresponding coupling product 10h in
59% yield. Benzyl deprotection of 10h with Pd/C in EtOH
gave 75% of the corresponding dihydroxy derivative 14b.
The benzyl deprotection was also carried out by treating
10h with TiCl4 in CHCl3 at room temperature for 48 h, but
it resulted in a mixture of the desired 14b along with singly
deprotected product and starting material 10h. Finally, lacto-
nization of 14b by refluxing it with MeOH/H2O (1:1) for 8 h
resulted in the desired target molecule 3,30,4-tri-O-methyl-
ellagic acid 1c in almost quantitative yield.
Between the intermediates 9 and 27, the former one can be
prepared easily in fewer steps compared to the latter one.
So, at first the intermediate 9 was utilized for the intramolec-
ular coupling reaction. Thus, a similar model compound 9a
was prepared in 89% yield from esterification of compounds
12 and 24 in the presence of DCC as shown in Scheme 5.
Treatment of 9a with Cu in the Ullmann coupling condition
gave the corresponding desired coupling product 10g in 32%
yield. Other reagents used for the Ullmann coupling such as
NiCl2,23 copper(II) thiophenecarboxylate (CuTC)24 were
also tested but did not give the desired coupling product.
The 59% yield for the intramolecular Ullmann coupling re-
action is noteworthy. Although intramolecular Ullmann
coupling of compounds like 27 is rather common, that of
compound 9 is rare. So far we know, the only such intramo-
lecular Ullmann coupling has been reported by Gottesegen
et al.26 where the diiodocompound was utilized and only
17–20% of the desired coupling product was obtained.
After the success in the intramolecular Ullmann coupling for
the model compound 9a, the actual precursor 9b for the
preparation of 3,30,4-tri-O-methylellagic acid was prepared
as shown in Scheme 6. The lower part (24) of 9b has already
been synthesized and the required bromide for the upper part
O
OH
Br
OMe
Br
OMe
OMe
OMe
MeO
OMe
O
O
Intramolecular
12
OMe
+
OMe
O
OMe
O
DCC (1.1 eq), DMAP
Ullmann Coupling
Br
(Cat), THF, 0 °C-r.t.,
6 h, 89%
O
O
O
Cu, 110 °C (3 h)
then 180 °C (18 h),
32%
OMe
OMe
OMe
Br
MeO
MeO
OMe
10g
OMe
9a
MeO
OH
OMe
24
Scheme 5. Model intramolecular Ullmann coupling.

10460
A. Alam, S. Tsuboi / Tetrahedron 63 (2007) 10454–10465
O
OMe
O
OMe
Br
O
OMe
Br
K2CO3(3 eq), BnCl (2.2 eq),
DMF, 55-60 °C, overnight
DBDMH (0.58 eq),
CHCl3, r.t., 4 h,
95% conv.
Br
+
HO
OH
HO
HO
OH
OH
OMe
21
OMe
OMe
85:15
O
OH
Br
O
OMe
Br
O
OMe
Br
O
OMe
Br
Br
Br
BnO
85:15
LiOH (2.5 eq),
+
+
MeOH/H2O (4:1)
r.t., 8 h
BnO
BnO
BnO
OBn
OBn
OBn
OBn
OMe
OMe
28
OMe
29, 15%, from 2
OMe
29
30, 81% from 2
OBn
OMe
Br
O
O
HO
OBn
O
OMe
Br
DCC (1.1 eq), DMAP (cat),
THF, 0 °C-r.t., 12 h, 78%
Br
+
30
O
MeO
OMe
OMe
24
MeO
OMe
9b
Scheme 6. Preparation of intermediate 9b for the intramolecular Ullmann coupling.
OBn
OH
OBn
OH
OMe
OMe
OMe
OMe
O
Pd/C, H2,
EtOH, r.t.,
O
O
O
MeOH/ H2O,
reflux, 8 h,
quantitative
OBn
O
OH
O
OBn
O
O
O
Cu, DMF,
Br
Br
O
reflux, 59%
48 h, 75%
O
O
O
OMe
OMe
OMe
MeO
MeO
MeO
MeO
OMe
OMe
OMe
10h
OMe
9b
14b
1c
3,3',4-tri-O-methylellagic acid.
Scheme 7. Synthesis of 3,30,4-tri-O-methylellagic acid by intramolecular Ullmann coupling.
3. Conclusion
very important for their use as important fragments for
many natural products as well as chiral reagents.27,28
The preparation of the challenging unsymmetric biaryl for
the synthesis of 3,30,4-tri-O-methylellagic acid has been
achieved finally by the intramolecular Ullmann coupling re-
action. This synthetic process will also be applicable for the
synthesis of other unsymmetric ellagic acid derivatives such
as 3,4,40-tri-O-methylellagic acid and other 3,30,4-tri-O-
methylellagic acid-40-glycoside derivatives (Fig. 1). So far
we know, this is the first report of the total synthesis of
3,30,4-tri-O-methylellagic acid from the simple building
block gallic acid. This synthetic access to the unsymmetric
ellagic acid derivatives will make it also possible to syn-
thesize any other unsymmetrically substituted ellagic acid
derivatives just by changing the functional groups in the
gallic acid derivatives 25 and 26. On the other hand, this
would also be a useful route for the preparation of the
unsymmetric biaryls; particularly those are from the highly
ortho-substituted aryl halides and of similar structural and
electronic environments. Reaction of 9b with copper in the
Ullmann coupling condition was almost clean and the puri-
fication on silica gel column chromatography was very sim-
ple. Cleavage of the lactone linkages of 10d–h, with some
chiral reagents give the axially chiral biaryls,27 which are
4. Experimental
4.1. General
All moisture sensitive reactions were carried out under nitro-
gen atmosphere using oven-dried glassware. Solvents were
dried over standard drying agents. Reactions were monitored
on TLC on silica gel 60 F254 and visualized under UV light
and/or 5% ethanolic solution of phosphomolybdic acid.
Flash chromatography was performed on silica gel (Merck,
60N, spherical, neutral, 40–50 mesh). Melting points were
determined with a Mel-Temp apparatus. IR was recorded
on a Thermo Nicolet Avatar 360T2 instrument using
1
either KBr or ATR. H NMR (300 MHz) and 13C NMR
(75 MHz) were recorded by Jeol AL 300 instrument. GC–
MS was studied in a Shimadzu GCMS-QP5000 instrument
(column length 30 m, Idm 0.25 mm, column temperature
50–250 ꢀC). Elemental analysis of all the new compounds
was carried out by Perkin Elmer 2400 series II CHNS/O
analyzer, whereas the spectral data of the known compounds
were matched with the references cited.

A. Alam, S. Tsuboi / Tetrahedron 63 (2007) 10454–10465
10461
4.2. 3,4,5-Trimethoxybenzoic acid (11)
J¼1.5 Hz), 7.52 (d, 1H, J¼1.5 Hz), 7.62 (s, 1H); 13C NMR
(CDCl3) d 52.22, 56.12, 56.28, 60.34, 61.04, 61.14, 61.21,
108.90, 110.96, 111.18, 112.93, 125.16, 126.71, 142.62,
145.37, 147.01, 151.81, 152.00, 152.30, 162.28, 165.68.
Anal. Calcd for C20H21BrO9: C, 49.50; H, 4.36. Found: C,
49.52; H, 4.32.
Gallic acid 2 (1.42 g) was treated with K2CO3 (5 equiv) and
MeI (5 equiv) in DMF at 50–55 ꢀC overnight to give methyl
tri-O-methyl gallate, which was treated with LiOH (233 mg,
3.0 equiv) in MeOH/H2O (1:1) at room temperature for 2 h.
After completion of the reaction, the solvent (methanol)
was removed in evaporator and the reaction mixture was
acidified with 2 M HCl and extracted with EtOAc. The or-
ganic layer was washed with water and then brine, dried
over MgSO4, condensed in evaporator to give the corre-
sponding acid 11 (1.74 g, 98%). The crude was very pure
and was used in the next step without further purification.
White needles; mp 166–167 ꢀC; IR (ATR): 2947, 2833,
2643, 2574, 2514, 1684, 1586, 1507, 1466, 1415, 1324,
4.4.2. 20-Bromo-50,60-dimethoxy-30-methoxycarbonyl-
phenyl 2-bromo-3,4,5-trimethoxybenzoate (9a). Bromo
acid component 12 (1 equiv) and the phenolic compound
24 (1 equiv) were treated with DCC (1.1 equiv) and
DMAP (cat) in THF as described in the general procedure
in Section 4.4 to give compound 9a in 89% yield as yellow
solid; mp 84–87 ꢀC; IR (ATR): 2938, 1749, 1732, 1565,
1488, 1429, 1330, 1215, 1199, 1171, 1131, 1096, 1001,
1268, 1224, 1182, 1122, 1001, 929, 858, 761, 715 cmꢁ1
;
738, 697 cmꢁ1; H NMR (CDCl3) d 3.93 (s, 3H), 3.94 (s,
1
1H NMR (CDCl3) d 3.93 (s, 6H), 3.95 (s, 3H), 7.38 (s, 2H);
13C NMR (CDCl3) d 56.12, 60.82, 60.88, 107.30, 124.04,
124.86, 152.86, 171.89.
9H), 3.95 (s, 3H), 3.98 (s, 3H), 7.42 (s, 1H), 7.62 (s, 1H);
13C NMR (CDCl3) d 52.22, 56.12, 56.28, 60.34, 61.04,
61.14, 61.21, 108.90, 110.96, 111.18, 112.93, 125.16,
126.71, 142.62, 145.37, 147.01, 151.81, 152.00, 152.30,
162.28, 165.68. Anal. Calcd for C20H20Br2O9: C, 42.58;
H, 3.57. Found: C, 42.40; H, 3.50.
4.3. 2-Bromo-3,4,5-trimethoxybenzoic acid (12)
Trimethoxybenzoic acid 11 (1.15 g, 5.42 mmol) was dis-
solved in 1.4 M NaOH solution (1.1 equiv) and solid
DBDMH (866 mg, 0.57 equiv) was added at room tempera-
ture and the reaction mixture was stirred for 36 h. After that
time period, it was acidified with 2 M HCl and extracted with
EtOAc. The organic layer was washed with water and then
brine, dried over MgSO4, condensed in evaporator to give
the corresponding bromide 12 (1.51 g, 96%). The product
was almost pure and was used in the next step without further
purification. White crystal; mp 82–85 ꢀC; IR (ATR): 2932,
1698, 1488, 1469, 1449, 1411, 1385, 1335, 1275, 1239, 1200,
4.4.3. 20-Bromo-50,60-dimethoxy-30-methoxycarbonyl-
phenyl 2-bromo-3,5-dibenzyloxy-4-methoxybenzoate
(9b). A mixture of compound 24 (1.0 equiv) and compound
30 (1.0 equiv) was treated with DCC (1.1 equiv) and DMAP
(cat) in THF for 12 h as described in the general procedure in
Section 4.4 to give compound 9b in 78% yield as gummy
solid; IR (ATR): 2938, 1749, 1732, 1565, 1488, 1429,
1330, 1215, 1199, 1171, 1131, 1096, 1001, 929, 909, 846,
1
738, 697 cmꢁ1; H NMR (CDCl3) d 3.91 (s, 3H), 3.94 (s,
3H), 3.95 (s, 3H), 3.99 (s, 3H), 5.08 (s, 2H), 5.23 (2H),
7.33–7.44 (m, 9H), 7.56–7.65 (m, 2H), 7.68 (s, 1H); 13C
NMR (CDCl3) d 52.54, 56.28, 56.30, 61.21, 61.23, 61.37,
61.39, 71.19, 75.47, 109.01, 111.56, 112.92, 113.29,
125.27, 126.61, 127.39, 127.46, 128.26, 128.29, 128.45,
128.51, 128.71, 135.94, 136.68, 142.60, 145.41, 147.76,
150.98, 151.32, 151.98, 162.26, 165.68. Anal. Calcd for
C32H28Br2O9: C, 53.65; H, 3.94. Found: C, 53.58; H, 3.90.
1
1166, 1111, 1026, 1001, 922, 775, 724 cmꢁ1; H NMR
(CDCl3) d 3.90 (s, 3H), 3.92 (s, 3H), 3.97 (s, 3H), 7.34 (s,
1H); 13C NMR (CDCl3) d 22.70, 22.73, 27.50, 27.52,
27.67, 27.70, 77.37, 77.68, 91.81, 113.47, 118.14, 118.65,
137.07. Spectral data were identical with the reported one.28
4.4. General procedure for the preparation of esters
8a,d–f, 9a,b
4.4.4. 30,50-Dimethylphenyl 2-bromo-3,4,5-trimethoxy-
benzoate (8d). Applying the general procedure in Section
4.4 (7 h), compound 8d was prepared from compounds 12
(1 equiv) and 16 (1 equiv) in 98% yield as white needles;
mp 84–85 ꢀC; IR (ATR): 2932, 2831, 1732, 1613, 1571,
1486, 1339, 1290, 1217, 1164, 1145, 1109, 1028, 1001,
947, 914, 852, 852, 683 cmꢁ1; 1H NMR (CDCl3, 300 MHz)
d 2.34 (s, 6H), 3.90 (s, 3H), 3.92 (s, 3H), 3.97 (s, 3H), 6.87 (s,
2H), 6.91(s, 1H), 7.34 (s, 1H); 13C NMR (CDCl3) d 21.14,
56.22, 60.99, 61.14, 110.09, 110.48, 112.95, 119.00,
126.72, 127.77, 139.34, 146.40, 150.48, 151.55, 152.33,
155.63, 164.72. Anal. Calcd for C18H19BrO5: C, 54.70; H,
4.85. Found: C, 54.68; H, 4.83.
To a solution of carboxylic acid (12, 17, 31, 1.0 equiv) in dry
THF was added the phenolic component (16, 19, 24,
1.0 equiv) followed by the addition of DCC (1.1 equiv)
and 4-dimethylaminopyridine (DMAP) (10 mol %) at
0 ꢀC. Then, the reaction mixture was stirred at room temper-
ature for 6–24 h under N2 atmosphere. After completion of
the reaction, solvent was reduced and the solid material de-
rived from DCC was separated by filtration and the thick
crude product was placed directly on the chromatographic
column, eluted with 20% EtOAc in hexane to give the
pure coupling products (8a,d–f, 9a,b) in good yields.
4.4.1. 50,60-Dimethoxy-30-methoxycarbonylphenyl
2-bromo-3,4,5-trimethoxybenzoate (8a). Compounds 12
(1 equiv) and 1325 (1 equiv) were treated with DCC
(1.1 equiv) and DMAP (cat) in THF for 6 h as described in
the general procedure in Section 4.4 to give compound 8a
in 75% yield as a light yellow solid; IR (ATR): 2936, 1743,
1730, 1512, 1480, 1429, 1330, 1215, 1199, 1170, 1133,
4.4.5. 20,30-Dimethoxyphenyl 5-benzyloxy 2-bromo-3-(di-
ethylcarbamoyloxy)-4-methoxybenzoate (8f). Com-
pounds 1725 (1 equiv) and 19 (1 equiv) (preparation of 19
is described later in Section 4.6) were treated with DCC
and DMAP in THF as described in the general procedure
in Section 4.4 (6 h) to give compound 8e in 86% yield, which
was dissolved in MeOH/H2O (2:1, 150 ml) and 2 M HCl was
added dropwise at room temperature. During the addition of
1
1096, 1001, 738, 695 cmꢁ1; H NMR (CDCl3) d 3.94 (s,
3H), 3.96 (s, 9H), 3.97 (s, 3H), 3.98 (s, 3H), 7.42 (d, 1H,

10462
A. Alam, S. Tsuboi / Tetrahedron 63 (2007) 10454–10465
HCl the reaction mixture became white instantly and after
a while it disappeared. The addition of HCl was continued
until the persistence of the white color. Then, the reaction
mixture was stirred for additional 2 h at room temperature.
The solvent (MeOH portion) was removed by evaporator
and the crude product was extracted with EtOAc, washed
with water and brine, dried over MgSO4, and condensed in
evaporator. Purification over silica gel chromatographic col-
umn gave the corresponding dihydroxy derivative. The dihy-
droxy derivative obtained was treated with NaH (1.5 equiv)
and MeI (1.5 equiv) in DMF at 55 ꢀC overnight to give
3.68 g of 8f (84% over two steps) as yellow solid; mp 110–
112 ꢀC; IR (ATR): 2965, 2923, 1752, 1724, 1492, 1467,
1399, 1340, 1278, 1255, 1243, 1203, 1162, 1143, 1106, 1081,
6-one (10e). Among the several runs, the best result was
obtained as follows. The bromo ester 8e (121 mg, 0.20 mmol)
was treated with Pd(OAc)2 (0.15 equiv), PPh3 (0.45 equiv),
and NaOPiv (2.0 equiv) at 120–125 ꢀC for 1 h as described
in the general procedure in Section 4.5 to give 7 mg of the de-
sired coupling product 10e (8%). Without further character-
ization of compound 10e it was converted to compound 10f
by treating it with 2 N HCl in MeOH at room temperature
for 4 h followed by methyl etherification by NaH and MeI
in DMF at 50 ꢀC overnight to give 80% of compound 10f.
Compound 10f was also prepared directly from compound
8f using the general procedure in Section 4.5 (Table 1).
Combined 10f was used for the next step without further
purification.
1
1074, 1001, 968, 790, 748, 706 cmꢁ1; H NMR (CDCl3,
300 MHz) d 1.23 (t, 3H, J¼7.2 Hz), 1.34 (t, 3H, J¼7.2 Hz),
3.42 (q, 2H, J¼7.2 Hz), 3.53 (q, 3H, J¼7.2 Hz), 3.81 (s,
3H), 3.89 (s, 3H), 3.97 (s, 3H), 5.18 (s, 2H), 6.82 (q, 2H,
J¼8.2 Hz), 7.07 (t, 1H, J¼8.2 Hz), 7.33–7.46 (m, 5H), 7.69
(s, 1H); 13C NMR (CDCl3) d 13.34, 14.17, 42.27, 42.56,
56.05, 56.08, 60.81, 60.85, 61.05, 61.09, 71.22, 110.32,
111.16, 114.60, 115.09, 123.46, 125.24, 127.48, 128.22,
128.63, 135.88, 141.13, 143.94, 144.08, 146.84, 150.92,
152.59, 153.79, 163.33. Anal. Calcd for C28H30BrNO8: C,
57.15; H, 5.14; N, 2.38. Found: C, 57.19; H, 5.04; N, 2.29.
4.5.3. 8-Benzyloxy-10-(diethylcarbamoyloxy)-3,4,9-tri-
methoxy-6H-dibenzo[b,d]pyran-6-one (10f). The bromo
ester 8f (100 mg, 0.16 mmol) was treated with Pd(OAc)2
(0.1 equiv), PPh3 (0.3 equiv), and NaOPiv (2.0 equiv) at
120 ꢀC for 55 min as described in the general procedure in
Section 4.5 to give 31 mg of the desired coupling product
10f (30% yield) as light yellow needles; mp 209–211 ꢀC;
IR (ATR): 1731, 1690, 1600, 1496, 1414, 1326, 1229,
1178, 1096, 997, 909, 729, 698 cmꢁ1; 1H NMR (CDCl3) d
1.23 (t, 3H, J¼7.2 Hz), 1.34 (t, 3H, J¼7.2 Hz), 3.42 (q, 2H,
J¼7.2 Hz), 3.53 (q, 2H, J¼7.2 Hz), 3.95 (s, 3H), 3.98 (s,
3H), 4.01 (s, 3H), 5.24 (s, 2H), 6.79 (dd, 1H, J¼1.5 Hz),
6.84 (dd, 1H, J¼1.5 Hz), 7.07 (t, 1H, J¼8.1 Hz), 7.32–
7.47 (m, 5H), 7.69 (s, 1H). Anal. Calcd for C28H29NO8: C,
66.26; H, 5.76; N, 2.76. Found: C, 66.00; H, 5.66; N, 2.60.
4.5. General procedure for the intramolecular Heck
coupling (preparation of 10d–f)
A flame dried flask was charged with the ester (8d–f,
1.0 equiv), the specified catalyst Pd(OAc)2/PPh3 (ratio
1:2), PdCl2(PPh3)2 or palladacycle, the specified base
NaOAc, NaOPiv (2 equiv) and the content of flask was dried
in vacuo for 1–2 h at 60 ꢀC. Dry DMA was added to yield
a suspension approximately 0.05 M of the starting material.
The mixture was degassed under argon and heated at 120–
130 ꢀC for the specified time. Then, it was allowed to cool
to room temperature. The reaction mixture was diluted
with EtOAc, washed sequentially with 2 M HCl and brine,
dried over MgSO4, and concentrated in vacuo. Flash chro-
matography on silica gel (10–15% EtOAc in hexane) gave
the desired lactones 10d–f.
4.6. 2-Ethoxybenzo[1,3]dioxol-4-ol (19)
A mixture of pyrogallol 18 (4.50 g, 35.7 mmol), CH(OEt)3
(17.8 ml, 3 equiv), and Amberlyst 15E (230 mg, 55% by
weight) in benzene (100 ml) was refluxed for 18 h in a flask
fitted with a Dean Stark trap for azeotropic removal of EtOH/
benzene to give 5.50 g of compound 19 (85%) as light brown
low melting solid, which turned dark red gradually after few
days. IR (ATR): 3214, 1630, 1504, 1484, 1473, 1375, 1226,
1
1111, 1033, 972 cmꢁ1; H NMR (CDCl3) d 1.27 (t, 3H,
J¼7.1 Hz), 3.76 (q, 2H, J¼7.2 Hz), 4.87 (br s, 1H), 6.48–
6.53 (m, 2H), 6.72–6.78 (m, 1H); 13C NMR (CDCl3)
d 14.77, 5944, 101.38, 110.81, 119.08, 122.00, 132.77,
138.92, 147.02.
4.5.1. 1,3-Dimethyl-8,9,10-trimethoxy-6H-dibenzo[b,d]-
pyran-6-one (10d). Among the several runs, the best result
was obtained by treating compound 8d with Pd(OAc)2
(10 mol %), PPh3 (0.2 equiv), and NaOAc (2.0 equiv) at
130 ꢀC for 24 h as described in the general procedure in Sec-
tion 4.5. After purification by silica gel chromatography, the
desired coupling product 10d was obtained in 42% along
with 40% of recovered starting material 8d. Light yellow
needles; mp 149–152 ꢀC; IR (ATR): 2942, 2835, 1728,
1617, 1593, 1477, 1383, 1339, 1288, 1208, 1163, 1110,
4.7. 3,5-Dibenzyloxy-4-methoxybenzoic acid (22)
Compound 21 (1.00 g, 5.06 mmol) was treated with K2CO3
(2.09 g, 3.0 equiv), BnCl (2.23 g, 3.0 equiv), in DMF at 55–
60 ꢀC for 12 h. After completion of the reaction, the crude
was extracted with diethyl ether, washed with water and
brine, dried over MgSO4, and concentrated to give 1.88 g
(98%) of the corresponding dibenzyloxy derivative. The
crude was then dissolved in MeOH/H2O (4:1) and LiOH
(475 mg, 4.0 equiv) was added, the mixture was stirred at
50 ꢀC for 5 h, and then it was acidified with HCl. Solvent
(MeOH portion) was removed in evaporator and the organic
part was extracted with EtOAc, washed with water and then
brine, and dried over MgSO4. Removal of solvent in evapo-
rator gave 1.73 g of pure 22 (96%) as a white solid; mp 130–
131 ꢀC; 1H NMR (CDCl3) d 3.96 (s, 3H), 5.18 (s, 4H), 7.30–
7.48 (m, 12H); 13C NMR (CDCl3) d 61.12, 71.19, 109.82,
1
1108, 1066, 1000, 856 cmꢁ1; H NMR (CDCl3) d 3.60 (s,
3H), 2.45 (s, 3H), 3.45 (s, 3H), 4.00 (s, 3H), 4.08 (s, 3H),
7.00 (m, 2H), 7.68 (s, 1H); 13C NMR (CDCl3) d 21.06,
23.30, 61.04, 61.47, 107.60, 114.16, 114.19, 118.75,
119.05, 123.48, 128.68, 136.93, 138.95, 148.53, 149.94,
150.61, 153.09, 161.49. Anal. Calcd for C18H18O5: C,
68.78; H, 5.77. Found: C, 69.00; H, 5.68.
4.5.2. 8-Benzyloxy-3,4-ethoxymethylenedioxy-10-(di-
ethylcarbamoyloxy)-9-methoxy-6H-dibenzo[b,d]pyran-

A. Alam, S. Tsuboi / Tetrahedron 63 (2007) 10454–10465
10463
123.92, 127.42, 128.05, 128.59, 136.56, 144.44, 152.23,
171.47.
3.93 (s, 3H), 5.19 (s, 2H), 7.15 (s, 1H); 13C NMR (CDCl3)
d 52.46, 56.17, 58.04, 60.97, 99.33, 109.30, 110.16,
127.89, 145.67, 148.54, 152.39, 166.48. Anal. Calcd for
C12H15BrO6: C, 43.00; H, 4.51. Found: C, 43.16; H, 4.35.
4.8. 3,5-Dibenzyloxy-4-methoxydiethylbenzamide (23)
Compound 22 (500 mg, 1.37 mmol) was refluxed with
freshly distilled SOCl2 (5 ml) in the presence of few drops
of DMF as catalyst for 2 h. After that, the excess SOCl2
was removed using water aspirator via an alkali trap. Then,
2–3 ml of benzene was added for the azeotropic removal of
the remaining SOCl2 and then dried in a vacuum pump.
CHCl3 (5 ml) was added to dissolve the crude acid chloride,
and Et3N (1.2 equiv) and Et2NH (1.2 equiv) were added suc-
cessively to this solution at room temperature. The reaction
mixture was stirred at room temperature for 4 h and then it
was poured in ice crushed, extracted with EtOAc, washed
with brine and water, and dried over MgSO4. Removal of
the solvent followed by chromatographic purification re-
sulted in 546 mg of compound 23 (98% over two steps). IR
(ATR): 2961, 2928, 1628, 1581, 1440, 1420, 1370, 1235,
4.11. 2-Bromo-3,5-dibenzyloxy-4-methoxybenzoic acid
(30)
The mono bromo derivative 30 was prepared from compound
21 using the selective hydrolysis process described in our ear-
lier report.25 Compound 21 in CHCl3 was treated with
0.58 mol equiv of DBDMH at room temperature for 4 h
that gave a mixture of the corresponding mono- and dibro-
mide. This mixture was then converted to the corresponding
benzyloxy derivatives (28 and 29) by treating the mixture
with BnCl (2.2 equiv) and K2CO3 (3.0 equiv) in DMF at
55–60 ꢀC overnight. The inseparable mixture of 28 and 29
was dissolved in MeOH/H2O (4:1) and treated with 2.5 equiv
of LiOH at room temperature for 8 h, which resulted in the
selective hydrolysis of 28 to the corresponding acid 30 and
it was separated from the unhydrolyzed dibromo ester 29
(15% from 21) by silica gel column chromatography (81%
of 30 from 21) as white powder; mp 133–135 ꢀC; IR
(ATR): 2932, 1698, 1576, 1566, 1413, 1366, 1328, 1269,
1239, 1096, 961, 907, 753, 733, 696 cmꢁ1; 1H NMR (CDCl3)
d 3.96 (s, 3H), 5.06 (s, 2H), 5.16 (s, 2H), 7.32–7.47 (m, 8H),
7.49 (s, 1H), 7.56–7.59 (m, 2H); 13C NMR (CDCl3/CD3OD)
d 60.95, 70.96, 75.17, 112.27, 127.175, 127.26, 127.95,
128.01, 128.11, 128.13, 128.16, 128.26, 128.30, 128.31,
128.34, 135.81, 136.39, 146.40, 151.10, 167.63. Anal. Calcd
for C22H19BrO5: C, 59.61; H, 4.32. Found: C, 59.40; H, 4.21.
Compound 29 was obtained as side product as colorless oil
(15%); IR (ATR): 2946, 2876, 1741, 1412, 1357, 1333,
1
1077, 1005, 737, 696 cmꢁ1; H NMR (CDCl3, 300 MHz)
d 0.74 (t, 3H, J¼7.1 Hz), 0.93 (t, 3H, J¼7.1 Hz), 2.67 (q,
2H, J¼7.1 Hz), 3.72 (q, 2H, J¼7.1 Hz), 3.91 (s, 3H), 5.14
(s, 4H), 6.62 (s, 2H), 7.30–7.44 (m, 10H); 13C NMR
(CDCl3) d 14.15, 20.98, 6.33, 60.91, 71.14, 106.37, 106.40,
127.18, 127.88, 128.52, 132.28, 136.82, 140.23, 152.42,
170.64. Anal. Calcd for C26H29NO4: C, 74.44; H, 6.97; N,
3.34. Found: C, 74.30; H, 6.85; N, 3.30.
4.9. 2,4-Dibenzyloxy-3-methoxy-6-diethylcarbamoyl-
benzeneboric acid (5a)
To a stirred solution of amide 23 (958 mg, 2.14 mmol) and
TMEDA (0.36 ml, 2.35 mmol) in dry THF (12 ml) was added
s-BuLi (2.14 ml, 1.1 M, 2.35 mmol, 1.1 equiv) dropwise over
15 min at ꢁ78 ꢀC. The stirring was continued for 1 h at
ꢁ78 ꢀC and a solution of B(OMe)3 (0.5 ml, 4.4 mmol) in
0.5 ml THF was added rapidly. The resultant mixture was al-
lowedto reach room temperature overnight under stirring. Af-
ter the completion of the reaction saturated aqueous NH4Cl
(4 ml) and water (3 ml) were added and the reaction mixture
was acidified to approximately pH 6 with 2 M aqueous HCl
(placing in a cooling bath). THF was removed in vacuo and
the crude was extracted with CH2Cl2, dried in evaporator,
and then in vacuum pump resulting in yellow floppy solid
5a (994 mg crude, 94%). The crude 5a was used in the next
step without any purification and structural characterization.
1
1219, 1087, 1002, 906, 732, 696 cmꢁ1; H NMR (CDCl3)
d 3.92 (s, 3H), 3.98 (s, 3H), 5.06 (s, 4H), 7.36–7.45 (m,
6H), 7.51–7.55 (m, 4H); 13C NMR (CDCl3) d 53.14, 61.62,
110.37, 128.49, 136.25, 149.99, 166.27.
4.12. General procedure for intramolecular Ullmann
coupling
Compounds 9a,b (1 equiv) were treated with 1 equiv (by
weight) of ordinary copper powder (without any sort of ac-
tivation) in DMF (10 ml/mmol) at 110 ꢀC for 3 h and then
at 180 ꢀC for 16–18 h. Progress of the reaction was moni-
tored by the highly fluorescent spot on TLC under UV light
for the desired coupling product. After completion of the re-
action, it was cooled at approximately 100 ꢀC and poured
into crushed ice. Then, the reaction mixture was diluted
with chloroform and the organic layer was separated,
washed three times with water and once with brine, dried
over MgSO4, and concentrated in evaporator. The crude
product was purified by flash column chromatography with
80% chloroform in hexane and then 100% chloroform. Dur-
ing column chromatography the movement of the desired
coupling product in the column can easily be monitored
using UV lamp, which gave highly fluorescent color.
4.10. Methyl 2-bromo-4,5-dimethoxy-3-methoxymethyl-
oxybenzoic acid (6)
Compound 2425 (400 mg, 1.37 mmol) was treated with
K2CO3 (380 mg, 2 equiv) and MOMCl (222 mg,
2.75 mmol, 2 equiv) in DMF (10 ml) under N2 atmosphere
at room temperature overnight. After the completion of
reaction, water was added and the crude was extracted
with EtOAc, washed with brine and water, and dried over
MgSO4. Removal of the solvent followed by chromato-
graphic separation gave 437 mg of the pure compound 6
(95%) as light yellow oil; IR (ATR): 3000, 2938, 2834,
1733, 1553, 1482, 1426, 1378, 1335, 1256, 1213, 1158,
4.12.1. Methyl 3,4,8,9,10-pentamethoxy-6-oxo-6H-di-
benzo[b,d]pyran-1-carboxylate (10g). Among the several
runs, the best result was obtained by treating dibromo ester
9a (100 mg, 0.18 mmol) with ordinary copper powder
(100 mg) at 110 ꢀC for 3 h and then at 175–180 ꢀC for 18 h
1
1111, 1072, 1002, 971, 924, 895, 816, 779, 733 cmꢁ1; H
NMR (CDCl3) d 3.66 (s, 3H), 3.88 (s, 3H), 3.98 (s, 3H),

10464
A. Alam, S. Tsuboi / Tetrahedron 63 (2007) 10454–10465
according to the general procedure described in Section 4.12
to give 21 mg of the desired coupling product 10g (32%) as
fluorescent solid; IR (ATR): 2934, 1745, 1732, 1560, 1477,
References and notes
1. (a) Castonguay, A.; Gali, H. U.; Perchellet, E. M.; Gao, X. M.;
Boukhar, M.; Jalbert, G.; Okuda, T.; Yoshida, T.; Hatano, T.;
Perchellet, T. Int. J. Oncol. 1997, 10, 367; (b) Perchellet,
J. P.; Gali, H. U.; Perchellet, E. M.; Klish, D. S.; Armbrust,
A. D. Basic Life Sci. 1992, 59, 783.
1
1330, 1214, 1199, 1165, 1091, 1001, 738, 695 cmꢁ1; H
NMR (CDCl3) d 3.60 (s, 3H), 3.77 (s, 3H), 3.99 (s, 3H),
4.00 (s, 3H), 4.04 (s, 3H), 4.05 (s, 3H), 7.25 (s, 1H), 7.67 (s,
1H).
2. Chang, X.-F.; Meng, Z.-M.; Chem, Z.-L. Phytochemistry 1998,
49, 2193.
4.12.2. Methyl 8,10-dibenzyloxy-3,4,9-trimethoxy-6-oxo-
6H-dibenzo[b,d]pyran-1-carboxylate (10h). The key inter-
mediate dibromo ester 9b (560 mg, 0.78 mmol) was treated
with ordinary copper powder (560 mg) in DMF according to
the general procedure described in Section 4.12 for 16 h to
give 436 mg of the desired coupling product 10h in 59%
yield as gummy solid; IR (ATR): 2940, 1735, 1734, 1565,
1422, 1335, 1201, 1168, 1171, 1130, 1096, 1001, 909,
3. (a) Stoner, G. D.; Kresty, L. A.; Carlton, P. S.; Siglin, J. C.;
Morse, M. A. Toxicol. Sci. 1999, 52, 95; (b) Chen, Z.;
Gundimeda, U.; Gopalakrishna, R. Proc. Annu. Meet. Am.
Assoc. Cancer Res. 1997, 38, A1395; (c) Choi, Y. H.;
Rezzuto, J. M.; Kinghorn, A. D.; Fornsworth, N. R. Planta
Med. 1988, 54, 511.
4. (a) Ikeda, M.; Sakai, T.; Tsuai, S.; Zuao, I.; Ryan, H.; Iyan, S.;
Kai, Y.; Kako, Y.; Tsukada, I.; Yanagisawa, M. Jpn. Kokai
Tokkyo Koho JP 08268890, 1996, 34 pp; (b) Das, M.;
Bickers, D. R.; Mukhtar, H. Carcinogenesis 1985, 6, 1409.
5. (a) Atta-Ur-Rahman; Ngounou, F. N.; Choudhary, M. I.; Malik,
S.; Makhmoor, T.; Nur-e-Alam, M.; Zareen, S.; Lontsi, D.;
Ayafor, J. F.; Sondengam, B. L. Planta Med. 2001, 67, 335;
(b) Bagchi, D.; Hassoun, E. A.; Bagchi, M.; Stohs, S. J. Free
Radical Biol. Med. 1993, 15, 217.
6. Aziz, M. A. R.; Azizur, M.; Quader, M. A.; Mosihuzzaman, M.
Dhaka Univ. J. Sci. Dhaka, Bangladesh 2003, 52, 29.
7. (a) Lee, J.-H.; Talcott, S. T. J. Agric. Food Chem. 2004, 52, 361;
(b) Vattem, D. A.; Shetty, K. Process Biochem. 2003, 39, 367.
8. Takasaki, M.; Konoshima, T.; Fujitani, K.; Yoshida, S.;
Nishimura, H.; Takuda, H.; Nishino, H.; Iwashima, A.;
Kozuka, M. Chem. Pharm. Bull. 1990, 38, 2737.
9. (a) Watanabe, T.; Isshiki, T.; Nakanishi, M. Jpn. Kokai Tokkyo
Koho JP 004277340, 2004, 13 pp; (b) Sumita, Y.; Sakai, S.;
Nakagawa, N.; Tanno, O. Jpn. Kokai Tokkyo Koho JP
2004262853, 2004, 12 pp.
1
738, 697 cmꢁ1; H NMR (CDCl3) d 3.90 (s, 3H), 3.95 (s,
3H), 3.95 (s, 3H), 4.00 (s, 3H), 5.06 (s, 2H), 5.24 (2H),
7.33–7.44 (m, 9H), 7.56–7.65 (m, 2H), 7.66 (s, 1H); 13C
NMR (CDCl3) d 52.55, 56.29, 56.32, 61.23, 61.25, 61.39,
71.21, 75.50, 111.57, 112.93, 113.31, 125.25, 126.63,
127.40, 127.66, 128.27, 128.27, 128.52, 128.51, 128.72,
135.94, 136.69, 142.60, 145.43, 147.76, 150.98, 151.32,
151.98, 162.26, 165.68. Anal. Calcd for C32H28O9: C,
69.06; H, 5.07. Found: C, 68.86; H, 5.13.
4.13. Methyl 8,10-dihydroxy-3,4,9-trimethoxy-6-oxo-
6H-dibenzo[b,d]pyran-1-carboxylate (14b)
Compound 10h (102 mg, 0.18 mmol) and Pd/C (36 mg,
10 mol %) in ethanol (5 ml) were stirred at room tempera-
ture under H2 atmosphere for 48 h. During this time period,
the reaction mixture was flushed occasionally with H2 using
the vacuum pump. After completion of the reaction, the solid
materials were separated by filtration over Celite followed
by washing with ethanol. After removal of the solvent, the
crude product was placed directly on the silica gel column
and eluted with chloroform to give 44 mg of compound
10. Alam, A.; Mamedov, V. A.; Gubaidulin, A. T.; Kalita, D.;
Tsuboi, S. Nat. Med. 2003, 57, 73.
11. Ikeda, M.; Sakai, T.; Tsuai, S.; Zuao, I. Jpn. Kokai Tokkyo
Koho JP 08268890, 1996.
1
14b (75%) as a gummy solid; H NMR (CDCl3) d 3.68 (s,
3H), 3.97 (s, 3H), 3.99 (s, 3H), 4.24 (s, 3H), 5.57 (s, 1H),
6.05 (s, 1H), 7.19 (s, 1H), 7.68 (s, 1H). Anal. Calcd for
C18H16O9: C, 57.45; H, 4.29. Found: C, 57.38; H, 4.20.
12. (a) Stanforth, S. P. Tetrahedron 1998, 54, 263; (b) Miller, J. A.;
Farrell, R. P. Tetrahedron Lett. 1998, 39, 6441; (c) Koch, K.;
Chambers, R. J.; Biggers, M. S. Synlett 1994, 347; (d)
Quesnelle, C. A.; Familoni, O. B.; Snieckus, V. Synlett 1994,
349; (e) Axton, C. A.; Billingham, M. E. J.; Bishop, P. M.;
Gallagher, P. T.; Hicks, T. A.; Kitchen, E. A.; Mullier, G. W.;
Owton, W. M.; Parry, M. G.; Scott, S.; Steggles, D. J.
J. Chem. Soc., Perkin Trans. 1 1992, 2203; (f) Tamao, K.;
Kodama, S.; Nakajima, I.; Kumada, M.; Minato, A.; Suzuki,
K. Tetrahedron 1982, 38, 3347; (g) Negishi, E.-I. Acc. Chem.
Res. 1982, 15, 340.
4.14. 3,30,4-Tri-O-methylellagic acid (1c)
Compound 14b was refluxed with MeOH/H2O (1:1) for 8 h to
give the desired product 1c almost in quantitative yield as
a light yellow solid; mp 280–282 ꢀC; IR (ATR): 3414, 1755,
1727, 1607, 1570, 1492, 1414, 1359, 1304, 1174, 1113,
1
1090, 1064, 986, 915, 755, 740 cmꢁ1; H NMR (CDCl3)
d 4.03 (s, 3H), 4.23 (s, 3H), 4.41 (s, 3H), 6.30 (s, 1H), 7.68
(s, 1H), 7.76 (s, 1H). Melting point and spectral data were
identical with that of isolated1 3,30,4-tri-O-methylellagic acid.
13. Suzuki, H.; Hisamatsu, Y. Synthesis 1997, 1273.
14. Lipshutz, B. H.; Liu, Z. P.; Kayser, F. Tetrahedron Lett. 1994,
35, 5567.
€
15. (a) Bringmann, G.; Heubes, M.; Breuning, M.; Gobel, L.;
Ochse, M.; Schoner, B.; Schupp, O. J. Org. Chem. 2000, 65,
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Acknowledgements
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Harayama, T.; Akiyama, T.; Nakano, Y.; Shibaike, K.
Heterocycles 1998, 48, 1989; (e) Harayama, T.; Shibaike, K.
Heterocycles 1998, 49, 191; (f) Harayama, T.; Akiyama, T.;
Nakano, Y. Chem. Pharm. Bull. 1997, 45, 1723; (g) See
We would like to thank Ms. Balaka Barkakaty of our group
for helping us in performing the elemental analysis of some
samples. Author A.A. greatly acknowledges the financial
support from the Ministry of Education, Culture, Sports,
Science, and Technology (Monbukagakusho), Japan for
the period 2001–2005.
€
Ref. 14; (h) Wiegand, S.; Schafer, H. J. Tetrahedron 1995,

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